title: Gold(III) complexes of pyridyl- and isoquinolylamido ligands: structural, spectroscopic, and biological studies of a new class of dual topoisomerase I and II inhibitors.
abstract: The structures, spectroscopy, and cytotoxicity of four novel nominally square-planar gold(III) chelates 1-4 with the general formula cis-AuCl2(X), where the ligand X is an anionic bidentate pyridyl- or isoquinolylamido chelating agent, are described. The Au-N(amido), Au-N(pyridyl), and Au-N(isoquinolyl) distances are 2.002(9)-2.016(3), 2.01(1)-2.037(3), and 2.037(3) Å, respectively. Density functional theory simulations afforded accurate gold(III) coordination geometries for 1-4 (bond distances and angles to within 5% of the X-ray values), while accurate transition energies were limited to those calculated in the UV spectral region. The complexes had variable stability in dimethyl sulfoxide: compound 3 (relatively rigid) was indefinitely stable, compounds 1 and 2 (conformationally flexible) slowly demetalated over 30 days, and 4 (extensively aromatic) formed an insoluble precipitate after 10 days (72 h in an aqueous buffer). The isoquinolylamido derivative 4 was sufficiently cytotoxic in the NCI-60 screen to undergo full five-dose testing. Notably low GI50 (1.8, 2.3, and 3.2 μM) and IC50 (4.0, 9.8, and 15 μM) values were recorded for the OVCAR-3, IGROV1, and SW-620 cell lines, respectively. Hierarchical cluster analysis employing the National Cancer Institute (NCI) data for known anticancer drugs and 4 revealed that compound 4 is mechanistically identical with the topoisomerase IIα (Top2) poison zorubicin and statistically similar to the topoisomerase IB (Top1) poisons camptothecin and 9-methoxycamptothecin. The Top2-catalyzed decatenation reaction of kinetoplast DNA was studied as a function of the concentration of 4: the compound acts as an interfacial poison of Top2 at low concentrations (<1 μM) and a catalytic inhibitor of the enzyme above 5 μM. Gel mobility shift assays (plasmid DNA substrate) showed that the catalytic inhibition of Top2 likely correlates with DNA binding by 4 at concentrations >5 μM. Compound 4 is also a catalytic inhibitor of Top1 at higher concentrations, consistent with DNA binding by the complex.
authors.affiliation: School of Chemistry and Physics, University of KwaZulu-Natal, Private Bag X01, Scottsville 3209, South Africa.
authors.forename: Colin R
authors.initials: CR
authors.lastname: Wilson
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Fagenson
authors.forename: Wanvipa
authors.initials: W
authors.lastname: Ruangpradit
authors.forename: Mark T
authors.initials: MT
authors.lastname: Muller
authors.forename: Orde Q
authors.initials: OQ
authors.lastname: Munro
mesh_terms: D000577:Amides / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D004247:DNA / Q000378:metabolism; D004264:DNA Topoisomerases, Type I / Q000378:metabolism; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D006801:Humans; D007546:Isoquinolines / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D009369:Neoplasms / Q000188:drug therapy; D050607:Organogold Compounds / Q000737:chemistry* / Q000494:pharmacology*; D059003:Topoisomerase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D000577:Amides; D000970:Antineoplastic Agents; D007546:Isoquinolines; D050607:Organogold Compounds; D059003:Topoisomerase Inhibitors; D004247:DNA; D004264:DNA Topoisomerases, Type I; D004250:DNA Topoisomerases, Type II